The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients, with nearly 200,000 cases per year in the US alone, mortality rates of 25-40%, and no effective pharmacotherapies. We recently identified and validated the presence of two distinct subphenotypes (also known as endotypes) of ARDS in two large randomized controlled trials. In an independent analysis of both datasets, there was strong evidence that there are two different endotypes within ARDS: a hyper-inflammatory endotype and a hypo-inflammatory endotype. These endotypes had strikingly different (1) clinical characteristics, (2) biomarker profiles, (3) clinical outcomes, and (4) treatment responses. Most notably, significant endotype-specific treatment responses were identified within a clinical trial previously thought to be negative. However, what remains unknown is whether these endotypes respond differently to other ARDS treatments and how to translate these promising findings to the bedside; likewise, the biology of the two endotypes remains incompletely understood. In the research proposed here, we will test the innovative central hypothesis that ARDS contains two distinct endotypes of disease, with different clinical and biologic characteristics and differing responses to therapy. We propose to test this hypothesis primarily within the framework of completed and ongoing NHLBI-funded ARDS randomized controlled trials, leveraging randomization to identify endotype-specific therapeutic responses. In Aim 1, we will use latent class analysis to identify ARDS endotypes in patients enrolled in two NHLBI-funded ARDS randomized controlled trials (the Statins for Acutely Injured Lungs (SAILS) clinical trial, already complete, and the Reevaluation Of Systemic Early neuromuscular blockade (ROSE) clinical trial, ongoing), in order to determine whether the endotypes respond differently to the therapies being tested in these trials. Also in Aim 1, we will test a practical, parsimonious model to identify ARDS endotypes in SAILS and ROSE, as well as in a more diverse ARDS cohort at UCSF. In Aim 2, we will identify specific differences in the biology of ARDS endotypes through analysis of novel candidate protein, lipid and metabolite biomarkers as well as high-throughput genomic sequencing, in the setting of the ROSE trial. Our research group is well-qualified to conduct this research by virtue of our expertise in pathogenesis-focused studies of human ARDS, our experience with the specific methods involved in the project, and our history of effective collaboration. Completion of these aims will have a high impact by identifying endotype-specific therapeutic responses, by developing practical approaches to endotype identification that can be directly translated to increase the efficiency and yield of future randomized controlled trials in ARDS, and by improving our understanding of the diverse biology of human ARDS, enhancing the likelihood that successful new therapeutics will be identified for each endotype.